The glutamate transporter GLT-1 (often called EAAT2 in human tissue) clears much of the glutamate in the cortex and hippocampus-regions of the brain that are heavily affected by AD. A significant body of data shows that GLT-1/EAAT2 is reduced and/or damaged in AD patients. Nonetheless, despite its critical neuroprotective functions in the brain, it is not known whether GLT-1 loss contributes significantly to the cognitive symptoms or pathology associated with AD. Addressing these key issues has been limited by: (i) the lack of an appropriate animal model that could be used to examine the biological significance of GLT-1 dysfunction in AD-related pathology;and (ii) the relative paucity of studies addressing GLT-1 dysfunction in the early stages of AD, thus impairing our ability to understand how GLT-1 dysfunction relates to the disease progression. To address these important issues we have crossed APPswe/PS1(E9 mice with mice lacking one allele of GLT-1 to produce a novel animal model of AD that has allowed us to begin examining the consequences of GLT-1 loss in the context of AD-related pathology. We have obtained data suggesting that partial loss of GLT-1 disturbs spatial memory and alters A[unreadable] (A[unreadable]) accumulation. We have also obtained new evidence suggesting that EAAT2 is aberrantly expressed in both prodromal and later-stage AD. Using APPswe/PS1(E9 mice with partial loss of GLT-1 we propose to investigate the mechanisms by which GLT-1 dysfunction interacts with mutant APP/PS1 to disturb cognition. We also propose to extend our understanding of EAAT2 dysfunction in AD patients by identifying early occurring, pathologically relevant oxidative post-translational modifications of GLT-1 in AD. Successful completion of these studies will increase our understanding of how damage to the primary glutamate clearance system of the brain is involved in AD pathogenesis and may provide new tools to facilitate the search for therapeutic strategies that target this important neurotransmitter in the brain. PUBLIC HEALTH RELEVANCE: Aging is the most significant risk factor associated with Alzheimer's disease (AD). Veterans make up an increasingly older segment of the population and thus are increasingly at risk of developing this debilitating disorder. Currently, there are limited clinical options for AD patients. Compounding this problem is the growing number of disappointing clinical trial results that collectively highlight the importance of developing new ideas about potential treatment strategies and the need to identify new therapeutic targets. From a clinical perspective there is evidence to suggest curbing excessive glutamate stimulation is helpful in treating AD. Glutamate is a normal neurotransmitter that brain cells use to communicate with each other. However, if glutamate is not quickly removed it becomes toxic. The glutamate transporter, GLT-1 (also called EAAT2) clears excess glutamate and thus prevents it from damaging brain cells. From a pathological perspective there is evidence that GLT-1 is reduced in AD and also damaged by other toxic molecules called A[unreadable] that accumulate in AD brains. This project proposes to use a novel animal model of AD that will test the importance of GLT-1 dysfunction in AD and help determine whether increasing GLT-1 could be a good candidate therapeutic approach. In addition we will attempt to determine how GLT-1 becomes damaged in human AD patients. Successful completion of the aims of this project will likely be an important first step toward finding new ways to treat or delay AD.